Testing the effect of the non-selective opioid PPL-138 in a model of alcohol relapse in the context of PTSD

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-09-03 DOI:10.1016/j.neuropharm.2025.110675

Sophia Draughon , Ali Idriss , Kylie Kealoha , Meira Gildin , Michael Lauber , Benjamin Carper , Lawrence Toll , Kelly M. Standifer , Andrea Cippitelli

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Abstract

Alcohol use disorder (AUD) is a frequent comorbidity in patients suffering from post-traumatic stress disorder (PTSD). Few therapeutic options are available for the individual disorders, and there are currently no drugs specifically shown to treat AUD in patients with comorbid PTSD. As PTSD has been associated with dysregulation of the brain's opioid system, our study aimed to examine the effects of a non-selective opioid compound, PPL-138, for use in co-morbid PTSD and AUD. Female and male Sprague-Dawley rats were trained to respond for alcohol in operant chambers. Following extinction, alcohol-seeking behavior was reinstated by cues previously associated with alcohol availability. All rats underwent Single Prolonged Stress (SPS) to induce PTSD-like manifestations, except for a male and female untraumatized group. Afterward, the anxiety-like behavior of all individual rats was assessed, and a second cue-induced reinstatement was conducted. Following subcutaneous PPL-138 testing (0.0, 0.1, 0.3, 1.0 mg/kg), female, but not male rats, who had escalated alcohol-seeking behavior after SPS, showed a reduction in their responses. Additionally, PPL-138 attenuated reinstatement in the subset of female rats that exhibited anxiety-like behavior. PPL-138 increased alcohol seeking in non-traumatized male rats, while leaving alcohol seeking of non-traumatized female rats unaltered. These results support the efficacy of pharmacological modulation of the opioid system in reducing both traumatic-like stress-induced escalation of alcohol-seeking behavior and cue-induced relapse associated with heightened anxiety, specifically in female rats. Classifying individuals based on traumatic stress-induced changes in alcohol-seeking behavior may provide a valuable model for evaluating pharmacological treatments for PTSD and AUD comorbidity.

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测试非选择性阿片类药物PPL-138在PTSD背景下酒精复发模型中的作用

酒精使用障碍（AUD）是创伤后应激障碍（PTSD）患者的常见合并症。针对个体障碍的治疗选择很少，目前还没有药物专门用于治疗合并PTSD的AUD患者。由于PTSD与大脑阿片系统的失调有关，我们的研究旨在研究一种非选择性阿片化合物PPL-138对合并PTSD和AUD的影响。雌性和雄性的Sprague-Dawley大鼠被训练在手术室内对酒精有反应。在消失之后，寻求酒精的行为被先前与酒精可得性相关的线索恢复。除未受创伤的雌雄大鼠外，所有大鼠均接受单次延长应激（SPS）诱导ptsd样表现。随后，评估所有个体大鼠的焦虑样行为，并进行第二次线索诱导恢复。在皮下PPL-138测试（0.0、0.1、0.3、1.0 mg/kg）后，SPS后寻求酒精行为升级的雌性大鼠（而不是雄性大鼠）的反应减少。此外，PPL-138在表现出焦虑样行为的雌性大鼠亚群中减弱了恢复。PPL-138增加了未受创伤的雄性大鼠对酒精的寻求，而未受创伤的雌性大鼠对酒精的寻求没有改变。这些结果支持阿片系统的药理学调节在减少创伤样压力诱导的酒精寻求行为升级和线索诱导的与高度焦虑相关的复发方面的功效，特别是在雌性大鼠中。基于创伤应激诱导的寻求酒精行为的改变对个体进行分类可能为评估PTSD和AUD合并症的药物治疗提供一个有价值的模型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).